Stabilized aromatic compounds



Patented Dec. 25, 1945 STABILIZED AROMATIC COMPOUNDS David Curtis, New York, N. Y.

No Drawing. Application February 25, 1942, Serial No. 432,322

Claims.

The present invention relates to methods and means for preserving aromatic compounds against oxidation and discoloration, and is a continuation in part of my application Serial No. 171,992, filed October 30, 1937, and which has issued as Patent No. 2,277,038 and my -application Serial No. 417,712, filed November 3, 1941, and which has issued as Patent No. 2,385,564.

It is the object of the present invention to provide a new group of substances which may be added to solutions of aromatic compounds having a tendency to oxidize and discolor in solution, to stabilize such aromatic compounds and retard their oxidation and discoloration.

It is another object of the present invention to form a series of new aromatic compounds which contain anti-oxidant groupings in their molecular structure, which will reduce the tendency of the product to auto-oxidation and discoloration.

Aromatic compounds, particularly those of the groups of phenylic, hydroxy-phenylic, phenylamino, hydroxy-phenyl-amino, phenyl-alkyl and alkanol amino, and hydroxy-phenyl-alkyl and alkanol amino compounds, nearly all have a tendency to oxidize and discolor, to a greater or lesser degree, in solution or in the presence of moisture.

Sulphites, bisulphites, hydrosulphites, metabisulphites and other sulphurous compounds, which are used as anti-oxidants for oxidizable aromatic compounds, such as named above, tend to undergo oxidation themselves, to a lesser or greater degree, thus losing their anti-oxidative protective properties and, upon occasion, themselves turning into compounds of greater irritative properties than the original compound. An outstanding example is the case of sodium bisulphite, NaHSOa, and meta-bisulphite, NazSzOe, which substances tend to undergo oxidation, losing their protective properties, when used to prevent oxidation and discoloration of epinephrine and epinephrine-like substances, and passing into the highly irritating, higher oxidation products of the sulphate, S04, ions.

I have found that by linking such sulphurous or sulphite compounds, to an aromatic aldehyde or a substituted aromatic aldehyde, the resultant addition products of greater stability and, consequently, of greater and more prolonged protective efiiciency, are obtained.

I have found that the addition of such aromatic aldehyde bi-sulphites to an aqueous solution of an oxidizable aromatic compound of the character described, has the efiect of greatly retarding the tendency of such aromatic compound to oxidize and discolor.

I have also found that by linking an aromatic aldehyde directly to the bi-sulphite of an oxidizable aromatic compound, an addition product of increased resistance to oxidation and discoloration is obtained.

I have also found that the addition of an oxidizable aromatic base, having an amino group or groups in the nucleus or in a side chain, to a solution of an aromatic aldehyde bisulphite, in suitable proportions, will result in the dissolving of the base to form a solution which is stable and resistant to oxidation and discoloration.

The aromatic aldehydes and their derivatives which could be used for the purposes of the present invention include the following: benzaldehyde and its hydroxy and substituted hydroxy derivatives, such as para-oxy-benzaldehyde, salicylaldehyde or ortho-oxy-benzaldehyde, resorcinolaldehyde, hydroxy methoxy benzaldehyde (C6H3.0H.OCH3.CHO 1,2,4-vanillic aldehyde), veratraldehyde (3,4 dimethoxy benzaldehyde, and other similar compounds capable of forming sulphite addition products, especially bisulphite addition products; also cinnamic aldehyde, anisaldehyde, amyl cinnamic aldehyde, phenyl acetaldehyde and others.

The sulphur compounds, with which the foregoing aromatic aldehydes are to be combined for the purposes of the present invention, are the oxidizable sulphur compounds, which include sulphurous acid ($023120), sulphites, and especially the bisulphites, hydrosulphites (to form aldehyde sulfoxylates, such as CsH5.C(OH)H.SO2H- benzaldehyde sulfoxylate), and meta-bisulphites, the last three of which will hereinafter be referred to as bisulphites, generally.

The aromatic aldehydes and the bi-sulphites combine in substantially equimolecular proportions, to form the desired addition products. Excess of either the aldehyde or the bi-sulphite compound may in certain cases be indicated. Some of .the bi-sulphite compounds are also capable of combining with more than one molar equivalent of the aromatic aldehyde. Thus, sodium hydrosulphite (NazSz04), may also combine with two molar equivalents of benzaldehyde, vanillin and others.

The aromatic aldehyde bi-sulphite compounds may partiallydissociate, in solution, to a lesser or greater extent, reversibly, into the original bi- .sulphite and aromatic aldehyde, or may imperfectly combine; but the reducing power of such a solution remains active for prolonged periods of time, thus accounting for the prolonged emcacy of such solutions as anti-oxidants.

Some specific examples oi the aromatic aidehyde bisulphite addition products of the present invention are: benzaldehyde in combination with sodium bisulphite, potassium bisulphite, lithium bisulphite, magnesium bisulphite, calcium bisulphite, respectively. and the like. Also benzaldehyde-potassiurn meta bisulphite benzaldehyde-sodium hydrosulphite (salami),

vanillic aldehyde-sodium bisulphite, benzaldehyde-hydrogen sulphite (CsHsCH(OH)SOa.H). Any of the other aromatic aldehydes maybe substituted for benzaldehyde and any alkali metals and alkaline earth metals may be substituted for sodium in the above combinations.

The anti-oxidants of the present invention may be used, in actual practice, in proportions varying from amounts less than the amount of substance to be preserved, to amounts greater than the amount of substance to be preserved, depending upon conditions of storage, type of container, conditions of use, and on whether a. stock compounding, either in solid or solution form is made,

which is to be subsequently adjusted or diluted to a desired concentration for use, or a final solution, ready for use, is made. The amount of antioxidant to be used will also depend on the nature nephrine or any of itssubstitutes, in a medium of 0.5% chlorbutenol, also containing 0.7% NaCl, 0.2% of sodium thiosulphate and from 0.1% to 0.2% of benzaldehyde sodium bisulphite may be added. Such a solution is eflectlvely preserved.

Many of the aromatic aldehyde bisulphite compounds have an acid reaction to methylred. Others range from. about neutral to methyl red'to alkalinity. The last includes cinnamic aldehyde bisulphite.

It is known, of course, that the stability of many of, the oxidizable aromatic compounds, such as epinephrine and epinephrine like compounds and others, is greater in acid solution. Therefore, it it is desired, an alkaline reacting aromatic aldehyde bisulphite may be adjusted to the acid side. Thi may be accomplished through the addition of S0: water or by mixing with an aromatic aldehyde bisulphite of lower pH value,

until the desired pH on the acid side is obtained.

, It is to be noted, however, that a certain amount and quantity oi. any other substances present in the solution with the substance to be preserved.

The anti-oxidant eflectiveness oi the variousaddition compounds or the present invention vary, to some extent, within limits of great utility, and they may be used singly or in combination in the same solution. t

Generally stated, the anti-oxidants of the present invention not only promote greater resistance to oxidation and discoloration than the bisulphites or similar substances heretofore -commonly used: but, in addition, accomplish such results, particularly in connection with such compounds as epinephrine or like substances, with addition of from 0.05% to 0.1% oi" any 01' the following: benzaldehyde-sodium bisulphite, paraoxy-benz'aldehyde-sodium bisulphite, benzaldehyde-potassium-meta-bisulphite; benzaldehydesodium-hydrosulphite, cinnamic aldehyde-sodium bisulphite, vanillin-sodium bisulphite, and others.

The amount of sodium bisulphite present in each epinephrine solution some sodium thiosulphate,

in addition to the aromatic aldehyde bisulphite compound. Thus to a 1.0% solution oi epi- (See: Proc. Soc. ExP'I..Biol. Med, v.'

Tainter, J.

of protection against oxidation is also afiorded by the alkaline reacting aromatic aldehyde bisulphite compounds. It is also to be noted that the easily oxidizable substances, such as epinephrine base, may be easily dissolved in an acid reacting aromatic aldehyde bisulphite compound solution, and will produce an alkaline solution of epinephrine of relative stability and freedom from discoloration, without the need for further modification. Thus, when 0.1 gm. of epinephrine base 'is dissolved in a solution containing 0.2 gm. of. benzaldehyde-sodium bisulphite, which is acid'to methyl red, and the solution made up -to 100 cc. with distilled water, a solution is obtained having a pH from 6.4 to 6.5, brom-thymol blue, which remains substantially colorless.

I have also found that the acid solution 0! an adrenalin salt, preserved with an acid reacting aromatic aldehyde bisulphite compound, when treated with a mild alkaline substance, such as 4 sodium bicarbonate, to adjust its pH from the acid side of methyl red to about 8.4 to 6.5, bromthymol blue, will remain colorless for a period of about 24 hours, even when completely exposed at room temperature, in more or less small volume; thus aiIording a chance to utiliz an alkaline epinephrine solution ,at'least for a clinical day.

To obtain even greater stability oi' alkaline solutions of oxidizable phenolic compounds, the following may be done: To a solution of an acid reacting aromatic aldehyde bisulphite compound,

a neutral or normal sulphite salt, such as sodium sulphite is added, preferably in an amountin excess over the molecular of the acid sulphite present in the particular addition product used.

' The reaction 01' the solution then becomes alka line to litmus paper.

Mild alkaline substance, such as alkaline sodium or potassium citrate and sodium bicarbonate and borax are then added to the solution. The anti-oxidant mixture thus prepared is then' added, in substantially standard proportions to the oxidizable phenolic compound. The final-mixture, if not already alkaline, may be further treated-with a mild alkaline substance, until the desired degree of alkalinity is obtained. Such final solution will remain colorless for considerable periods 01' time.

Thus, for instance, 2.5 gms. of sodium sulphite are added to a solution of 3 gms. of benzaldehyde-sodium bisulphite in 200 cc. of water. This is followed by the addition and dissolving of 2.5 gms. of sodium citrate and 1 gm. otsodium bicarbonate. 2 cc. of the resulting solution may accuses be added to preserve 100 cc. of a 0.1% solution of epinephrine made alkaline with sodium bicarbonate. The amount of anti-oxidant thus added. in terms of active aldehyde-bisulphite-sulphite combination present, amounts to about 0.05%.

The above anti-oxidant preparation is particularly suitable for the preservation of oxidizable hydroxy-phenolic compounds, such as hydroquinone and others. Thus, when about 7.5 cc. of the above anti-oxidant solution (containing about 0.2 gm. of the active bisulphite-sulphite) are added to 2 gms. of hydroquinone in 100 cc. of water and the solution made alkaline with sodium bicarbonate, the hydroquinone solution thus treated will remain colorless longer than a similar solution of hydroquinone, made alkaline with sodium'bicarbonate, to which 0.2 gm. of sodium sulphite alone has been added.

It isto be noted, particularly, that when the above anti-oxidant preparation is added to' a solution containin as the active ingredients. a combination of hydroquinone and para-methylamino-phenol sulphate, and also containing the usual amount of sodium sulphite and sodium carbonate, a solution capable of reducing silver and remaining colorless for a long period of time is produced.

Solutions of epinephrine and like substances. in the presence ofanaesthetics. such as in' a standard procaine solution, have, heretofore, been stabilized by the use of sodium hydrogen sulphite, which is, of course, subject to more or less rapid auto-oxidation. I have, heretofore, also used, with better results, sodium thiosulphate together with sodium bisulphite or sodium sulphite, preferably the former; the latter group of substances being added to overcome the tendency of sodium thiosulphate to become decomposed because of its great sensitivity to acidic substances, certain of which are found or may develop in such anaesthetic-epinephrine solutions. Such mixture of anti-oxidants, as I have previously developed it, is a vast improvement over the use of sodium thiosulphate alone, as indicated in the Bull. So. Pharm., v. 31, pp. 88-94, 1924. I

I have found, however, that through the substitution of aromatic aldehyde bisulphite for the sodium bisulphite. in my above sodium thiosulphate-sodium bisulphite mixture, a still greater improvement is obtained, due to the reater stability of such aromatic aldehyde-bisulphite as compared with the ordinary bisulphite.

The anti-oxidant mixture of sodium or similar thiosulphate and aromatic aldehyde-bisulphite may be used to stabilize epinephrine and epinephrine-like substances in numerous anaesthetic salt solutions, such as in solutions containing the hydrochloride, or the tartrate, the citrate, the gluconate, the malate, the cinnamate, the sulphite, the sulphate, the hydrogen sulphite, the thiosulphate and other organic and inorganic acid salts of procaine and other anaesthetic bases.

Of the epinephrine-like and other vaso-constrictor substances which may be stabilized in anaesthetic solutions by my above combination of anti-oxidants, the following are some that may be named: 3,4 dihydroxy-phenyl-propanolamine, 3,4 dihydroxy-phenyl-ethyl-methylamine, in the form of their salts, as hydrochlorides, bitartrates, citrates, gluconates, cinnamates, and the like.

As an example of an anaesthetic-epinephrine solution, preserved in accordance with the foregoing description, the following may be given:

Procaine hydrochloride 2% Chlorbutanol 0.5% Sodium chloride 0.66% or less Potassium sulphate 0.33%

Epinephrine salt, figured to base content 1:60,000 to 1:30,000

Sodium thiosulphate (anhydrous) 0.1% to 0.15% Benzaldehyde sodium bisulphite 0.05% to 0.1% In distilled water.

Instead of procaine hydrochloride, any other of the above enumerated anaesthetic salts may be used, figured to 2% of salt or base content. or other requisite concentration. Instead of epinephrine, any of its substitutes may be used.

In addition to the aromatic aldehyde-sodium bisulphite, ordinary sodium' bisulphite or'so lution of benzaldehyde-sodium bisulphite. The pH of the resultant solution is 6.4 to 6.5, brom thymol blue.

Similarly, oxidation resistant compounds of the amino-phenylic substances may be prepared by first forming a bisulphite of the amino-phenylic base, which then becomes analogous to sodium bisulphite (NaHSOa), the amino-phenylic bisulphite having the probable general formula of R.H2SO3, R standing for the amino-phenylic radicle. This amino-phenylic bisulphite may then be. combined with an aromatic aldehyde, in the manner that sodium bisulphite combines with the same aromatic aldehyde. The general formula of the final compound probably is:

men

R standing for the aromatic nucleus of the aldehyde and R for the aniino-phenylic base, similar to the aromatic aldehyde-sodium bisulphite compound, which has the formula of OSOaNa OH As specific examples of the method for making the aromatic aldehyde-amino-phenylic-bisulphite compounds, the following may be given:

0.183 gm. of epinephrine base is suspended in 25 cc. of 0.5% chloretone water. Sufficient S02 water is then added, drop by drop, while stirring, until a clear solution is obtained. Generally a little more than the molecular equivalent of S02 may be added (or slightly more than 0.064 gm. of S02, in this example). After the solution is clear, an equimolecular amount of benzaldehyde, 0.1061 gm. is added and the mixture agitated until it clears. When diluted with chloroetone water to form a 0.1% solution, with respect to :base, the pH registers about 6.3, brom-thymol blue.

When the above synthesis is conductedin a sufficiently small volume of water, a precipitate of the newly formed compound is produced, which may be separated. The compound has the probable formula of CsH5CH(OH) S03.HR. R standing for the epinephrine base radicle. The compound is relatively stable in solution, but may be additionally preserved the further addition of an aromatic aidehyde-hisulphite.

Similarly benzaldehyde-ephedrine bisulphite may be prepared. This compound is readily solcaine bisulphite. This solution is alkaline to litmus.

Benzaldehyde-benzocain bisulphite may be prepared by dissolving benzocain base in a small amount of alcohol and adding the solution to 80: water containing slightly more than the molar equivalent of $02. The mixture is agitated until a white precipitate of 'benzocain bisulphite is formed. The molar equivalent of benzaldehyde is now stirred A yellow reddish mass first terms, which upon continued stirring, passes into a snowy-white crystalline material.

Using orthoform (methyl para oxy-metaminobenzoate instead of benzccaine, benzaldehydeorthoform hisulphite is obtained, a product soluble in water and being acid to methyl red.

The foregoing aromatic aldehyde-phenylic- .amino'bisulphites may also .be formed from the amino-phenylic salts, by first neutralizing the acid radicle to which the phenylic base is attached by the addition of sodium bicarbonate or other suitable alkaline substance and then proceeding as previously indicated in connection with the method of formationfrom the base.

As a specific example: To 0.333 gm. oi epinephrine bitartrate (containing 0.183 gm. of

epinephrine base), dissolved in 10 cc. of water 0.084 gm. of sodium bicarbonate is added. The mixture is stirred and to it is quickly added 2.2

cc. of a 3% solution of SOz containing slightly, more than the molar equivalent of 0.064 gm. of 4 S02) and 0.1061 gm. of benzaldehyde is then stirred in, until solution is complete.

It is also possible to link a phenyl-amino compound of the character described to a previously formed aromatic aldehyde compound of sul- Dhurous acid.

Para methyl-amino phenol sulphate itself, which is acid in solution, may beefiectively preserved by benzaIdehyde-sodium bisulphit alone.

Thus, a 2% aqueous solution of the para methyL- amino phenyl sulphate may be preserved and its discoloration prevented for a long period or time by the addition of 0.1% of benzaldehyde-sodium bisulphite.

This completes .the description of the preserving methods of the present invention and of the resulting products. It will be readily understood that within the principles herein discussed, many modifications and variations, as to the methods employed, the products preserved and the products used and formed for preserving, may be made without the use 01 the inventive facultiesuand within the spirit and scope or the present invention and of the claims hereto appended.

What I claim asmy invention is: v 1. As a new composition oi" matter, a preparation containing an epinephrine salt and an addition product of an aromatic aldehyde with a salt selected from the group consisting or bisulphite a s. hydrosulphite 881128- and metabisulphite salts.

2. As a new composition of matter, a preparation containing an anaesthetic salt, an oxidizable kyl-substituted amino-aromatic compounds hav-' .ing a 'hydroxyl grouping attached to the arcmatic nucleus and having the amino grouping in an alcohol chain which is attached to the aromatic nucleus; alkyl and alkamine carboxylic acid esters of p-amino-vbenzoic compounds; and hydroxylated amino-aromatic compounds and hydroxylated, alkyl-su-bstituted amino aromatic compounds having a hydroxyl grouping and the amino grouping attached to the aromatic nucleus, and, as an anti-oxidant, an addition product of an aromatic aldehyde with asalt selected from the group consisting o1 bisulphite salts, hydrosulphite salts and metabisulphite salts.

- 4. A'composition' or matter containing an oxidizable phenyl compound from the group consisting of aromatic compounds having a hydroxyl grouping in the aromatic nucleus; alkyl and alkamine carboxylic acid esters or p-amino-benzoic compounds; hydroxylated amino-aromatic compounds and hydroxylated, alkyl-substituted amino-aromatic compounds having a hydroxyl grouping attached to the aromatic nucleus and having the amino grouping in an alcohol chain which is attached to the aromatic nucleus; and hydroxylated amino aromatic compounds and hydroxylated, alkyl-substituted amino-aromatic compounds having the hydroxyl grouping and the amino grouping attached to the aromatic nucleus, and, as an anti-oxidant, an addition product of an aromatic aldehyde and a metallic bi- 'sulphite salt.

5. A composition of matter containing an oxidizable phenyl compound from the group consisting of aromatic compounds having a hydroxyl grouping in the aromatic nucleus; alkyl and alkamin esters of p-amino benzoic acid; hydrox- 'ylated amino aromatic compounds and hydroxylated. alkyl-substituted amino-aromatic compounds having a hydroxyl grouping in the aromatic nucleus and the amino grouping in an alcohol chain attached to the aromatic nucleus; and hydroxylated amino-aromatic compounds and hydroxylated, alkyl-substituted amino-aromatic compounds'having a hydroxyl grouping and the amino grouping attached to the aromatic nucleus, and, as an anti-oxidant. anaddition product of an aromatic'aldehyde and a salt selected from.

the group consisting of 'bisulphite salts, hydrosuiphite salts and metabisulphite salts and a normal sulphite salt.

DAVID CURTIS. 

